Ergoline analogues

ABSTRACT

This invention relates to pharmaceutically acceptable ergoline analogues and salts thereof. In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/941,506, filed on Sep. 9, 2022, which is a continuation ofInternational Application No. PCT/IB2022/050355, filed on Jan. 17, 2022,each of which is incorporated by reference herein, PCT/IB2022/050355claiming the benefit of priority to GB Application No. 2100549.1, filedon Jan. 15, 2021, GB Application No. 2107104.8, filed on May 18, 2021,and GB Application No. 2116270.6, filed on Nov. 11, 2021.

FIELD OF THE INVENTION

This invention relates to pharmaceutically acceptable ergoline analoguesand salts thereof. In particular, though not exclusively, the inventionrelates to formulations and uses of the same as a medicament.

BACKGROUND TO THE INVENTION

Ergoline is the main structure for a class of alkaloids including thewell-known lysergic acid diethylamide (LSD). The chemical formula of LSDis:

Various synthetic modifications to the structure of LSD have been madein the prior art. However, such modifications often result in a decreasein activity. Ineffective docking/binding of these compounds to theappropriate receptors may result from such structural modifications.

There remains a need in the art for ergoline analogues, and improvedcompositions and uses thereof.

SUMMARY

Herein disclosed is a compound of Formula (I) wherein:

-   -   X is selected from H or C₁₋₆ alkyl (optionally, X is methyl or        isopropyl); and    -   Y is selected from a bond, O, CONH, NH, N(C₁₋₆ alkyl),        A-(CH₂)_(n)—B, wherein        -   A is O, NH or N(C₁₋₆ alkyl), wherein        -   B is a bond, O, or NH, wherein        -   n is 1 to 4; and    -   Z is selected from H, OH, NH₂, NHC₁₋₆ alkyl, N(C₁₋₆ alkyl)₂,        C₁₋₆ alkyl, C₆₋₁₀ aryl, SO₂—C₁₋₆ alkyl, SO₂—C₆₋₁₀ aryl, C₃-C₁₀        heteroaromatic or heterocyclic group comprising one, two or        three heteroatoms independently selected from O and N; and    -   wherein X and Z are different;        or is a pharmaceutically acceptable salt thereof.

In a first aspect of the invention, there is provided compound ofFormula (I) wherein:

-   -   X is selected from methyl or isopropyl; and    -   Y is selected from a bond, O, CONH, NH, N(C₁₋₆ alkyl),        A-(CH₂)_(n)—B, wherein        -   A is O, NH or N(C₁₋₆ alkyl), wherein        -   B is a bond, O, or NH, wherein        -   n is 1 to 4; and    -   Z is selected from H, OH, NH₂, NHC₁₋₆ alkyl, N(C₁₋₆ alkyl)₂,        C₁₋₆ alkyl, C₆₋₁₀ aryl, SO₂—C₁₋₆ alkyl, SO₂—C₆₋₁₀ aryl, C₃-C₁₀        heteroaromatic or heterocyclic group comprising one, two or        three heteroatoms independently selected from O and N; and    -   wherein X and Z are different;    -   or a pharmaceutically acceptable salt thereof.

In an embodiment the alkyl group is straight, branched or a cyclic alkylgroup.

In an embodiment the alkyl group is a straight chain alkyl group. In anembodiment the alkyl group contains 1, 2 or 3 halogens.

In an embodiment X is methyl.

In an embodiment X is isopropyl.

In an embodiment Y is selected from a bond, O, CONH, NH or NCH₃.

In an embodiment Y is A-(CH₂)_(n)—B, wherein

-   -   A is O or NH, wherein    -   B is a bond, O or NH, wherein    -   n is 1 to 4.

In an embodiment n is 2 or 3.

In an embodiment Z is selected from pyridine, morpholine, SO₂—CH₃,SO₂-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and2-oxa-5-azabicyclo[2.2.1]heptane.

In an embodiment Y—Z together form the group:

-   -   O—(CH₂)₃—N(CH₃)₂    -   NH—(CH₂)₂—OH    -   NH—(CH₂)₃—OH    -   NH—(CH₂)—OCH₃    -   NH—(CH₂)₃—SO₂CH₃    -   NH—(CH₂)₂—NH—SO₂CH₃, or    -   O—(CH₂)₂—NH—SO₂CH₃.

In an embodiment Y—Z together form the group:

-   -   NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH—SO₂-Phenyl,        NCH₃—SO₂-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or        2-oxa-5-azabicyclo[2.2.1]heptane.

In an embodiment there is provided one or more compounds selected from:

Number IUPAC SMILES Structure 001 (1S,2R)-2-(1H- indol-3-yl)cyclopropan-1- aminium [H]N1C([H])═C(C2═C1C ([H])═C([H])C([H])═C2[H])[C@@]1([H])C([H]) ([H])[C@]1([H])[N+]([H]) ([H])[H]

002 (4R,6R,7R)-4-[N′- (3-hydroxypropyl)- N-methylhydrazine- carbonyl]-6-methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- [H]OC([H])([H])C([H])) [H])C([H])([H])N([H])N(C(═O)[C@]1([H])C([H])═ C2C3═C4C(N([H])C ([H])═C4C([H])([H])[C@@]2([H])[N@+]([H])(C([H]) ([H])[H])C1([H])[H])═C ([H])C([H])═C3[H])C([H])([H])[H]

pentaen-6-ium 003 (4R,6R,7R)-6- methyl-4- [methyl(pyridin-4-yl)carbamoyl]- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(C3═C([H])C([H])═NC([H])═C3[H])C([H]) ([H])[H])C([H])([H])[N @@+]([H])(C([H])([H])[H])[C@]1([H])C2([H])[H]

004 (4R,6R,7R)-6- methyl-4-[N- methyl-N′-(oxan-4- yl)hydrazine-carbonyl]-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N)[H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1)[H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C1 ([H])C([H])([H])C([H]))[H])OC([H])([H])C1([H])[H]

005 (4R,6R,7R)-4-[N′- (benzenesulfonyl)- N,N′- dimethylhydrazine-carbonyl]-6- methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N(C([H])([H])[H])S(═O)(═O)C3═C([H]) C([H])═C([H])C([H])═C3 [H])C([H])([H])[H])C([H])([H])[N@@+]([H])(C) [H])([H])[H])[C@]1([H]) C2([H])[H]

006 (4R,6R,7R)-4-[N′-(3- methoxypropyl)-N- methylhydrazine-carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N)[H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1)[H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C)[H])([H])C([H])([H])C([H]) ([H])OC([H])([H])[H]

007 (4R,6R,7R)-6- methyl-4- {methyl[(1R,5S)- 8-oxa-3-aza-bicyclo[3.2.1]octan- 3-yl]carbamoyl}- 6,11-diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H])[C@@]4([H])O[C@]([H]) (C([H])([H])C4([H])[H]) C3([H])[H])C([H])([H])[H])C([H])([H])[N@@+] ([H])(C([H])([H])[H])[C @]1([H])C2([H])[H]

008 (4R,6R,7R)-6- methyl-4- [methyl(oxan-4- yloxy)carbamoyl]-6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14-pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13)C1═C([H])[C@@]([H]) (C(═O)N(OC3([H])C([H]) ([H])C([H])([H])OC([H])([H])C3([H])[H])C([H])) [H])[H])C([H])([H])[N@ @+]([H])(C([H])([H])[H])[C@]1([H])C2([H])[H]

009 (4R,6R,7R)-4-[N′- (benzenesulfonyl)-N- methylhydrazine-carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N)[H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1)[HJ)[H])═C([H])C([H])═C 3[H])C([H])([H])[H])S(═O) (═O)C1═C([H])C([H])═C([H])C([H])═C1[H]

010 (4R,6R,7R)-4-[N′-(3- methanesulfonylpropyl)- N-methylhydrazine-carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N)[H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1)[H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C)[H])([H])C([H])([H])C([H]) ([H])S(═O)(═O)C([H]) ([H])[H]

011 (4R,6R,7R)-6- methyl-4- {[methyl(phenyl- carbamoyl)amino]carbonyl}-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca-1(16),2,9,12,14- pentaen-6-ium [H]N(C(═O)N(C(═O)[C @]1([H])C([H])═C2C3═C4C(N([H])C([H])═C4C ([H])([H])[C@@]2([H]) [N@+]([HJ)(C([H])([H])[H])C1([H])[H])═C([H])C ([H])═C3[H])C([H])([H]) [H])C1═C([H])C([H])═C([H])C([H])═C1[H]

012 (4R,6R,7R)-4-[N′-(2- methanesulfonamido- ethyl)-N-(propan-2-yl)hydrazinecarbonyl]- 6-methyl-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H])C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+])[H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3 [H])C([H])(C([H])([H])[H])C([H])([H])[H])C([H]) ([H])C([H])([H])N([H])S (═O)(═O)C([H])([H])[H]

013 (4R,6R,7R)-4-[N′- (2-hydroxyethyl)- N-(propan-2-yl)hydrazinecarbonyl]- 6-methyl-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]OC([H])([H])C([H]))[H])N([H])N(C(═O)[C@] 1([H])C([H])═C2C3═C4 C(N([H])C([H])═C4C([H])([H])[C@@]2([H])[N@+] ([H])(C([H])([H])[H])C1 ([H])[H])═C([H])C([H])═C3[H])C([H])(C([H])) [H])[H])C([H])([H])[H]

014 (4R,6R,7R)-6-methyl- 4-{[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5- yl](propan-2- yl)carbamoyl}-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H])[C@@]4([H])OC([H][H]) [C@]3([H])C4([H])[H]) C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H]) [N@@+]([H])(C([H])) [H])[H])[C@]1([H])C2)[H])[H]

015 (4R,6R,7R)-6-methyl- 4-{[(1S,4S)-2-oxa-5- azabicyclo[2.2.2] octan-5-yl](propan-2- yl)carbamoyl}-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H])[C@@]4([H])OC([H])([H]) [C@]3([H])C([H])([H]) C4([H])[H])C([H])(C([H])([H])[H])C([H])([H])[H]) C([H])([H])[N@@+]([H]) (C([H])([H])[H])[C@]1([H])C2([H])[H]

016 (4R,6R,7R)-4-[(2- methanesulfonamido- ethoxy)(propan-2-yl)carbamoyl]-6- methyl-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(C([H])([H])C([H])([H])ON(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H])[C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3[H])C([H])(C([H])([H]) [H])C([H])([H])[H])S(═O) (═O)C([H])([H])[H]

017 (4R,6R,7R)-4-{[3- (dimethylazanium yl)propoxy](propan-2-yl)carbamoyl}-6- methyl-6,11- diazatetra- cyclo[7.6.1.0²,⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(OC([H])([H])C)[H])([H])C([H])([H])[N+] ([H])(C([H])([H])[H])C)[H])([H])[H])C([H])(C([H]) ([H])[H])C([H])([H])[H]) C([H])([H])[N@@+][H])(C([H])([H])[H])[C@] 1([H])C2([H])[H]

018 (4R,6R,7R)-6- methyl-4- [pentyl(propan-2- yl)carbamoyl]-6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14-pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13)C1═C([H])[C@@]([H]) (C(═O)N(C([H])([H])C([H]) ([H])C([H])([H])C([H])([H])C([H])([H])[H])C) [H])(C([H])([H])[H])C([H]) ([H])[H])C([H])([H])[N@@+]([H])(C([H])([H]) [H])[C@]1([H])C2([H]) [H]

019 (4R,6R,7R)-6-methyl- 4-[(propan-2- yl)carbamoyl]-6,11- diazatetra-cyclo[7.6.1.0²,⁷ ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium[H]N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N([H]) C([H])═C4C([H])([H])[C@@]2([H])[N@+]([H]) (C([H])([H])[H])C1([H]) [H])═C([H])C([H])═C3[H])C([H])(C([H])([H])[H]) C([H])([H])[H]

In an embodiment there is provided one or more compounds selected from:

Number Structure 020

021

022

023

024

025

As calculated and described further herein below, compounds 001 to 019have good ‘Docking Scores’ (Kcal/mol) to target the modelled receptorsand are synthetically accessible. As such, compounds 001 to 019 aredemonstrated to be synthetically accessible and useful as medicamentsfor appropriate conditions involving the target receptors, or relatedreceptors with the associated corresponding conditions.

Synthetic Docking scores Number Accessibility (Kcal/mol) 001 2.35 −8.579002 4.39 −13.446 003 4.19 −12.761 004 4.55 −12.399 005 4.72 −12.957 0064.51 −12.330 007 5.63 −12.323 008 4.62 −12.549 009 4.59 −12.506 010 4.64−11.908 011 4.43 −12.275 012 4.84 −12.818 013 4.51 −12.370 014 5.76−12.593 015 5.89 −12.395 016 4.92 −12.366 017 4.98 −12.362 018 4.62−12.146 019 4.09 −11.855

In an embodiment there is provided a composition comprising apharmaceutically effective amount of a compound as described previously.

In an embodiment, the nitrogen atom on the core six-membered ring is notmethylated (e.g. Compound 025 is not methylated). In an embodiment, thenitrogen atom on the core six-membered ring is methylated (e.g. Compound025 is methylated).

In an embodiment the composition comprises a dosage amount in the rangeof 0.05 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.1 mg to 50 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.5 mg to 25 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.5 mg to 10 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 1 mg to 10 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 1 mg to 8 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 3 mg to 15 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.005 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.001 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the rangeof 0.0005 mg to 100 mg.

The level of the active agent can be adjusted as required by need forexample to suit a certain patient group (e.g. the elderly) or theconditions being treated.

In an embodiment the composition is formulated in a dosage form selectedfrom: oral, transdermal, inhalable, intravenous, rectal dosage,intranasal, intramuscular, or any other parenteral form.

In an embodiment the composition is formulated in a dosage form selectedfrom: oral, transdermal, inhalable, intravenous or rectal dosage

It is advantageous to be able to deliver the active agent in differentforms, for example to suit a certain patient group (e.g. the elderly) orthe conditions being treated.

In an embodiment the composition is formulated in a dosage form selectedfrom: tablet, capsule, granules, powder, free-flowing powder, inhalablepowder, aerosol, nebulised, vaping, buccal, sublingual, sublabial,injectable, or suppository dosage form.

In an embodiment the powder is suitable for administration by inhalationvia a medicament dispenser selected from a reservoir dry powder inhaler,a unit-dose dry powder inhaler, a pre-metered multi-dose dry powderinhaler, a nasal inhaler or a pressurized metered dose inhaler.

In an embodiment the powder comprises particles, the particles having amedian diameter of less than 2000 μm, 1000 μm, 5001 μm, 250 μm, 100 μm,50 μm, or 1 μm.

In an embodiment the powder comprises particles, the particles having amedian diameter of greater than 500 μm, 250 μm, 100 μm, 50 μm, 1 μm or0.5 μm.

In an embodiment the powder comprises particles, and wherein the powderhas a particle size distribution of d10=20-60 μm, and/or d50=80-120 μm,and/or d90=130-300 μm.

The nature of the powder can be adjusted to suit need. For example, ifbeing made for nasal inhalation, then the particles may be adjusted tobe much finer than if the powder is going to be formulated into agelatine capsule, or differently again if it is going to be compactedinto a tablet.

In an embodiment the compound is in the form of a salt which isamorphous or crystalline.

In an embodiment the salt is in a polymorphic crystalline form.

In an embodiment the salt is a benzoate, fumarate, citrate, acetate,succinate, halide, fluoride, chloride, bromide, iodide, oxalate, ortriflate salt, optionally the salt is the chloride, benzoate or fumaratesalt.

In an embodiment the salt is formulated into a composition for mucosaldelivery. In an embodiment, the salt is a benzoate salt.

For the salt, the dosage amount is the equivalent amount of the freebase delivered when the salt is taken. So 100 mg dosage amount may forexample correspond to 117 mg of a hydrochloride salt (i.e. bothproviding the same molar amount of the active substance). The greatermass of the salt needed is due to the larger formula weight of thehydrogen chloride salt. Similarly, for the deuterated or trituratedversion of the compounds of the invention (also considered within thescope of the invention), a slight increase in mass can be expected dueto the increased formula weight of these isotopic compounds.

Amorphous and crystalline substances often show differentchemical/physical properties, e.g. improved rate of dissolution in asolvent, or improved thermal stability. Similarly, different polymorphsmay also show different and useful chemical/physical properties.

In an embodiment the composition comprises one or more pharmaceuticallyacceptable carriers or excipients.

In an embodiment the composition comprises one or more of: mucoadhesiveenhancer, penetrating enhancer, cationic polymers, cyclodextrins, TightJunction Modulators, enzyme inhibitors, surfactants, chelators, andpolysaccharides.

In an embodiment the composition comprises one or more of: chitosan,chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC),n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl(QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin,Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), humanneutrophil elastase inhibitor (ER143), sodium taurocholate, sodiumdeoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmiticacid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capricacid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybeanlecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecylmaltoside, EDTA, lactose, cellulose, and citric acid.

In an embodiment the compound or composition defined herein above foruse in a method of treatment of a human or animal subject by therapy.

In an embodiment the method of treatment is a method of treatment of:

conditions caused by dysfunctions of the central nervous system,

conditions caused by dysfunctions of the peripheral nervous system,

conditions benefiting from sleep regulation (such as insomnia),

conditions benefiting from analgesics (such as chronic pain),

migraines,

trigeminal autonomic cephalgias (such as short-lasting unilateralneuralgiform headache with conjunctival injection and tearing (SUNCT),and short-lasting neuralgiform headaches with cranial autonomic symptoms(SUNA)),

conditions benefiting from neurogenesis (such as stroke, traumatic braininjury, Parkinson's dementia),

conditions benefiting from anti-inflammatory treatment,

depression,

anxiety,

substance use disorder,

addictive disorder,

gambling disorder,

eating disorders,

obsessive-compulsive disorders, or

body dysmorphic disorders,

optionally the condition is SUNCT and/or SUNA.

Treatment of the above conditions may be beneficially improved by takingthe invention.

In an embodiment the method of treatment is a method of treatment ofmore than one of the above conditions, for example, the method oftreatment may be a method of treatment of depression and anxiety.

In an embodiment the composition is administered one or more times ayear.

In an embodiment the composition is administered one or more times amonth.

In an embodiment the composition is administered one or more times aweek.

In an embodiment the composition is administered one or more times aday.

In an embodiment the composition is administered at such a frequency asto avoid tachyphylaxis.

In an embodiment the composition is administered together with acomplementary treatment and/or with a further active agent.

In an embodiment the further active agent is a psychedelic compound,optionally a further tryptamine.

In an embodiment the further active agent is a psychedelic compound,optionally a tryptamine.

In an embodiment the further active agent is psilocybin, psilocin or aprodrug thereof.

In an embodiment the complementary treatment is psychotherapy.

In an embodiment, there is provided a composition comprising apharmaceutically effective amount of a compound as described herein foruse in a method of treatment of treatment resistant depression.

In an embodiment, there is provided a nasal inhalation compositioncomprising a pharmaceutically effective amount of a compound asdescribed herein for use in a method of treatment of treatment resistantdepression.

Treatment of the above conditions may be beneficially improved by takingthe invention together with some complementary treatments; also thesetreatments may occur much less regularly than some other treatments thatrequire daily treatments or even multiple treatments a day.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assayresults for compounds 018 and 019.

FIG. 2 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1(IP₁) assay results for compounds 018 and 019.

FIG. 3 shows serotonin (2a, 2b and 2c receptors) calcium (Ca²⁺) assayresults for compounds 018 and 019.

FIG. 4 shows serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assayresults for compounds 018 and 019.

FIG. 5 shows serotonin 2b receptor B-arrestin assay results forcompounds 018 and 019.

DETAILED DESCRIPTION OF THE INVENTION

The crystal structures of the serotonin receptor were retrieved from theProtein Data Bank (www.rcsb.org) [PDB ID: 5TVN and 6WGT for 5-HT2B and5-HT2A respectively. Both proteins were prepared for docking ofcandidate ligands. Briefly, hydrogens were added, bond orders wereassigned, and loops and side chains were filled. Restrain minimizationwas performed using Optimized Potentials for Liquid Simulations(OPLS2005) force field until the RMSD reached 0.3 Å from the initialgeometry in order to improve steric clashes. Additionally, otherpossible receptor targets were used and prepared structurally as furtherindicated below.

Binding Pocket Analysis

Only two crystallographic structures are available from the Protein DataBank of the 5-HT2A and 5-HT2B receptors in complex with(8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide whichrepresents an active isoform of LSD. The binding pockets were analysedto determine the interaction between the receptor residues and theligands structure. Homologies modelling was applied to determinesimilarities in several receptor/protein targets. Moreover the bindingpocket was analysed by intrinsic dynamic Domains (IDD) methodology tofurther verify the residues on the receptors that most contribute to theactivity of the binding site.

Ligands

Initial consideration regarding anti-inflammatory properties,vaso-constriction, vaso-dilation and psychedelic effects wereconsidered.

Upon further analysis the scaffold, lysergic acid amide deprived of theC8 amide group was used. Analysis of key attachment points wasimplemented and subsequently R-groups were assigned to the initialscaffold. The R-groups were selected from a library of fragments. Thecompounds were filtered by Lipinski's rule of five (RO5), rapidelimination of swill (REOS) and pan assay interference compounds (PAINS1, 2, and 3).

The resulting ligand structures were prepared for docking by identifyingstereoisomers with protonation states of pH7±2.

Docking

In the binding pocket residues containing hydroxyl and thiol groups wererotated to account for some flexibility of the pocket in the first stageof rigid docking. Subsequently the best compounds were used for flexibledocking in order to further simulate a physiological state of thereceptors.

Molecular Dynamics Simulation

Simulations for both receptors were implemented on the basis of the topligand binding scores. All of the simulations were carried out using theMD Desmond package. Available crystal structures were used. The receptorand ligand complexes were set up in an orthorhombic box using a buffercondition of 10 Å. The orientations of the membranes (if available) werefrom the Orientation of Protein in Membranes (OPM) database. Ions wereneutralized for the system, salt was added at a concentration of 0.15 MNaCl, and OPLS 2005 was used for the force field. Long-rangeelectrostatic interactions were calculated with the Ewald method using acut-off of 9 Å for Van der Waals and Coulomb interactions. Thesimulation was carried out in an isothermal, isobaric ensemble (NPT)with an initial temperature of 300° K and 1 bar of pressure. Thetemperature followed the Nose-Hoover method and the pressure wascontrolled by the Martyna-Tobias-Klein protocol. The simulation was setfor 200 ns and trajectories were recorded every 100 ps. The defaultrelaxation protocol for the system was used. Representative structureswere extrapolated from the simulation at 0, 100, and 200 ns.

Chemical and Other Pharmacokinetic Properties

The compounds were analysed computationally regarding suitable chemicalcharacteristic and pharmacokinetic parameters and compared across knownagonists of mainly the two serotonin receptors (5-HT2A and 2B). Severalalgorithms were implemented.

Identified Ergoline Analogues

The structures of selected ergoline analogues are shown in the tableabove and further described below:

Properties of Selected Ergoline Analogues

Various properties of selected ergoline analogues are detailed in thetables below, followed by an explanation of the properties:

Number Formula MW Heavy atoms 001 C11H13N2 173.23 13 002 C20H27N4O2355.45 26 003 C22H23N4O 359.44 27 004 C22H29N4O2 381.49 28 005C24H27N4O3S 451.56 32 006 C21H29N4O2 369.48 27 007 C23H29N4O2 393.5 29008 C22H28N3O3 382.48 28 009 C23H25N4O3S 437.53 31 010 C21H29N4O3S417.54 29 011 C24H25N4O2 401.48 30 012 C22H32N5O3S 446.59 31 013C21H29N4O2 369.48 27 014 C24H31N4O2 407.53 30 015 C25H33N4O2 421.56 31016 C22H31N4O4S 447.57 31 017 C24H36N4O2 412.57 30 018 C24H34N3O 380.5528 019 C19H24N3O 310.41 23

Number Aromatic heavy atoms Csp3 Rotatable bonds 001 9 0.27 1 002 9 0.456 003 15 0.27 3 004 9 0.5 4 005 15 0.29 5 006 9 0.48 7 007 9 0.52 3 0089 0.5 4 009 15 0.26 5 010 9 0.48 7 011 15 0.25 5 012 9 0.5 8 013 9 0.486 014 9 0.54 4 015 9 0.56 4 016 9 0.5 8 017 9 0.54 8 018 9 0.54 7 019 90.42 3

Number H-bond acceptors H-bond donors MR 001 0 2 54.73 002 3 4 107.22003 2 2 112.66 004 3 3 114.65 005 4 2 129.16 006 3 3 111.95 007 3 2121.35 008 3 2 112.93 009 4 3 124.26 010 4 3 119.83 011 2 3 123.06 012 54 127.44 013 3 4 112.03 014 3 2 126.16 015 3 2 130.96 016 5 3 125.73 0172 3 127.73 018 1 2 122.49 019 1 3 98.36

Number TPSA LOGP XLOGP3 001 43.43 1.64 1.36 002 72.8 2.73 1.65 003 53.432.55 2.7 004 61.8 2.63 2.39 005 86.3 3.14 3.26 006 61.8 3.1 2.19 00753.01 3.04 2.7 008 59 2.88 2.67 009 95.09 2.59 3.07 010 95.09 2.61 1.71011 69.64 2.85 3.94 012 107.12 2.16 1.88 013 72.8 2.85 2.1 014 53.013.15 3.14 015 53.01 3.05 3.49 016 104.32 2.28 2.17 017 54.21 3.9 3.46018 40.54 3.46 4.81 019 49.33 2.71 2.83

Number WLOGP MLOGP Consensus Log P 001 1.27 −2.13 0.91 002 −0.41 −2.180.68 003 1.3 −1.7 1.52 004 0.38 −1.74 1.13 005 2.01 −1.41 1.67 006 0.24−1.96 1.15 007 0.1 −1.53 1.21 008 0.81 −1.74 1.39 009 1.67 −1.62 1.42010 0.72 −2.1 0.89 011 1.74 −0.94 2.01 012 0.61 −2.67 0.59 013 −0.03−1.96 0.96 014 0.48 −1.32 1.51 015 0.87 −1.11 1.73 016 1.04 −2.67 0.82017 −0.06 −5 1.01 018 2.67 −0.49 2.98 019 0.76 −1.58 1.53

ESOL Solubility ESOL Solubility Number ESOL Log S (mg/ml) (mol/l) 001−2.22 1.05 0.00607 002 −2.94 0.405 0.00114 003 −3.98 0.0374 0.000104 004−3.68 0.0788 0.000207 005 −4.71 0.0088 0.0000195 006 −3.3 0.187 0.000507007 −4.01 0.0382 0.0000972 008 −3.87 0.0519 0.000136 009 −4.51 0.01340.0000306 010 −3.27 0.222 0.000532 011 −4.85 0.00565 0.0000141 012 −3.480.148 0.000331 013 −3.3 0.183 0.000496 014 −4.3 0.0203 0.0000498 015−4.6 0.0105 0.0000249 016 −3.67 0.0959 0.000214 017 −4.27 0.02210.0000535 018 −5.01 0.00376 0.00000987 019 −3.64 0.0713 0.00023

Solubility Class (II-method) Solubility Number (ESOL) Log S (mg/ml) 001Soluble −1.87 2.31 002 Soluble −2.79 0.574 003 Soluble −3.48 0.12 004Soluble −3.33 0.179 005 Moderately soluble −4.75 0.0081 006 Soluble−3.12 0.279 007 Moderately soluble −3.47 0.135 008 Soluble −3.56 0.105009 Moderately soluble −4.73 0.00808 010 Soluble −3.32 0.199 011Moderately soluble −5.1 0.00317 012 Soluble −3.75 0.0791 013 Soluble−3.26 0.203 014 Moderately soluble −3.92 0.0487 015 Moderately soluble−4.29 0.0218 016 Soluble −3.99 0.0454 017 Moderately soluble −4.280.0216 018 Moderately soluble −5.39 0.00154 019 Soluble −3.52 0.0929

Number Solubility (mol/l) II method Class Pgp substrate 001 0.0134 Verysoluble No 002 0.00161 Soluble Yes 003 0.000335 Soluble Yes 004 0.000469Soluble Yes 005 0.0000179 Moderately soluble Yes 006 0.000756 SolubleYes 007 0.000342 Soluble Yes 008 0.000275 Soluble Yes 009 0.0000185Moderately soluble Yes 010 0.000476 Soluble Yes 011 0.0000079 Moderatelysoluble Yes 012 0.000177 Soluble Yes 013 0.000551 Soluble Yes 0140.000119 Soluble No 015 0.0000518 Moderately soluble Yes 016 0.000101Soluble Yes 017 0.0000525 Moderately soluble Yes 018 0.00000404Moderately soluble Yes 019 0.000299 Soluble Yes

CYP1A2 CYP2C19 CYP2C9 Number inhibitor inhibitor inhibitor 001 Yes No No002 No No No 003 Yes No No 004 No No No 005 No No Yes 006 No No No 007No No No 008 No No No 009 No No Yes 010 No No No 011 No Yes Yes 012 NoNo No 013 No No No 014 No No No 015 No No No 016 No No No 017 No No No018 No Yes Yes 019 No No No

CYP2D6 CYP3A4 Number inhibitor inhibitor log Kp (cm/s) 001 No No −6.39002 No No −7.3 003 No No −6.58 004 No No −6.93 005 No Yes −6.74 006 NoNo −7 007 Yes No −6.78 008 No No −6.74 009 No No −6.79 010 No No −7.63011 No No −5.95 012 No No −7.69 013 No No −7.06 014 Yes No −6.56 015 YesNo −6.39 016 No No −7.49 017 No No −6.36 018 No No −5.21 019 No No −6.18

Number Lipinski #violations Ghose violations Veber violations 001 0 0 0002 0 1 0 003 0 0 0 004 0 0 0 005 0 0 0 006 0 0 0 007 0 0 0 008 0 0 0009 0 0 0 010 0 0 0 011 0 0 0 012 0 0 0 013 0 0 0 014 0 0 0 015 0 1 0016 0 0 0 017 0 0 0 018 0 0 0 019 0 0 0

Bioavailability Number Egan violations Muegge violations Score 001 0 10.55 002 0 0 0.55 003 0 0 0.55 004 0 0 0.55 005 0 0 0.55 006 0 0 0.55007 0 0 0.55 008 0 0 0.55 009 0 0 0.55 010 0 0 0.55 011 0 0 0.55 012 0 00.55 013 0 0 0.55 014 0 0 0.55 015 0 0 0.55 016 0 0 0.55 017 0 0 0.55018 0 0 0.55 019 0 0 0.55

Number PAINS alerts Brenk alerts Leadlikeness violations 001 0 0 1 002 00 1 003 0 0 1 004 0 0 1 005 0 0 1 006 0 0 1 007 0 0 1 008 0 1 1 009 0 01 010 0 0 1 011 0 0 2 012 0 0 2 013 0 0 1 014 0 0 1 015 0 0 1 016 0 1 2017 0 1 2 018 0 0 2 019 0 0 0

Number Synthetic Accessibility Docking scores (Kcal/mol) 001 2.35 −8.579002 4.39 −13.446 003 4.19 −12.761 004 4.55 −12.399 005 4.72 −12.957 0064.51 −12.330 007 5.63 −12.323 008 4.62 −12.549 009 4.59 −12.506 010 4.64−11.908 011 4.43 −12.275 012 4.84 −12.818 013 4.51 −12.370 014 5.76−12.593 015 5.89 −12.395 016 4.92 −12.366 017 4.98 −12.362 018 4.62−12.146 019 4.09 −11.855

Naming and Strings

IUPAC name=compound name

Smile=Smile naming convention of compound

Formula=Chemical formula compound

Physiochemical Properties

MW=Molecular weight

Heavy atoms=Atoms with significantly higher atomic scattering factorthan the others present

Aromatic heavy atoms=As above referring to the ring structures

Csp3=the ratio of sp3 hybridized carbons over the total carbon count ofthe molecule (> or equal to 0.25)

Rotable bonds=Bonds in the molecule that can rotate

H-Bonds acceptor=Bonds that can accept hydrogen ion

H-Bonds doner=Bonds that can donate hydrogen ion

MR=Molecular refractivity

TPSA=topological polar surface area

Lipophilicity

LOG P=partition coefficient for ionisable compounds. An approximationimplemented by CHARMM version c36 (Chemistry at Harvard MacromolecularMechanics)

X LOG P=another atomistic method with correction factors from: Cheng, T.et al. Computation of Octanol-Water Partition Coefficients by Guiding anAdditive Model with Knowledge. J Chem Inf. Model 47, 2140-2148 (2007).

W LOG P=is another Log P using the Wildman method described in: Wildman,S. A. & Crippen, G. M. Prediction of Physicochemical Parameters byAtomic Contributions. J. Chem. Inf. Model. 39, 868-873 (1999).

M LOG P=Moriguchi topological method for partition coefficient.Moriguchi, I., Shuichi, H., Liu, Q., Nakagome, I. & Matsushita, Y.Simple Method of Calculating Octanol/Water Partition Coefficient. Chem.Pharm. Bull. 40, 127-130 (1992).

General Log p=In order to increase the accuracy of the Log P o/W theabove methods were used and a general estimation of these values wascondensed in “General Log P” column

Solubility

ESOL Log S=Aqueous solubility by ESOL method: Delaney, J. S. ESOL:Estimating Aqueous Solubility Directly from Molecular Structure. J.Chem. Inf. Model. 44, 1000-1005 (2004)

ESOL Solubility (mg/ml)=quantification of solubility by SwissADME

ESOL Solubility (mol/1)=as above

Solubility class for ESOL method=solubility in aqueous solution

II methods Log S=Solubility method based on: Ali, J., Camilleri, P.,Brown, M. B., Hutt, A. J. & Kirton, S. B. Revisiting the generalsolubility equation: in silico prediction of aqueous solubilityincorporating the effect of topographical polar surface area. J. Chem.Inf. Model. 52, 420-428 (2012).

Pharmacokinetics

Pgp substrate=P glycoprotein, this describes if the compound is asubstrate of glycoprotein associated with the permeability of biologicalmembranes.

The below subfamilies of the cytochrome P450 determine drug eliminationand metabolism in association with Pgp data: CYP1A2 inhibitor, CYP2C19inhibitor, CYP2C9 inhibitor, CYP2D6 inhibitor, CYP3A4 inhibitor,

Drug-Likeness

Lipinski violations

Ghose violations

Veber violations

Egan violations

Muegge violations

Bioavailability Score (The Abbot Bioavailability Score)

Synthesis

“PAINS (Pan-assay interference compounds)=Baell, J. B. & Holloway, G. A.New substructure filters for removal of pan assay interference compounds(PAINS) from screening libraries and for their exclusion in bioassays.J. Med. Chem. 53, 2719-2740 (2010).”

“Brenk alerts=Brenk, R. et al. Lessons learnt from assembling screeninglibraries for drug discovery for neglected diseases. ChemMedChem 3,435-444 (2008).”

“Lead likeness violations=based on: Teague, S., Davis, A., Leeson, P. &Oprea, T. The Design of Lead like Combinatorial Libraries. Angew. Chem.Int. Ed. Engl. 38, 3743-3748 (1999).”

“Synthetic Accessibility=based on two papers: Fukunishi, Y., Kurosawa,T., Mikami, Y. & Nakamura, H. Prediction of synthetic accessibilitybased on commercially available compound databases. J Chem Inf Model 54,3259-3267 (2014).

Ertl, P. & Schuffenhauer, A. Estimation of synthetic accessibility scoreof drug-like molecules based on molecular complexity and fragmentcontributions. J. Cheminform. 1, 8 (2009). From 1 to 10 with 1 easy and10 complex”

Docking Scores (Kcal/mol)

Scores are reported for docking to the target, the highest negativenumber indicates a better binding pose of the ligand in the receptor(5-HT2A) (similar scores are related to the 5-HT2B).

Abbreviations

-   5-HT #=5-hydroxytryptamine receptor # HH1R=Histamine H1 receptor-   A #AR=Alpha-# adrenergic receptor M.Rec=Membrane receptor-   B #AR=Beta-# adrenergic receptor MAPTau=Microtubule-associated    protein tau-   CP450 #=Cytochrome P450 # MBLP #=Muscleblind-like protein #-   CXCCRT3=C—X—C chemokine receptor type 3 Na-Dep=Sodium-dependent-   D(#)DR=D(#)DR Trans.=Transporter-   D(#)DR=D(#) dopamine receptor Unc=Unclassified-   Enz=Enzyme where #=a number

Compound/Target Data

Further Information Regarding Targets Screened

The table below details the range of targets that selected ergolineanalogues were screened against and the results.

Number Number of sim. of sim. Compound Uniprot Gene ChEMBL By cmpdscmpds Target Number Target ID Code ID Homology Probability (3D) (2D)Class 001 5HTR2A P28223 HTR2A 224 No 1 76 193 M. Rec 5HTR2C P28335 HTR2C225 No 1 71 151 M. Rec 5HTR2B P41595 HTR2B 1833 No 1 71 151 M. Rec5HTR1A P08908 HTR1A 214 Yes 0.74 12 528 M. Rec 5HTR1D P28221 HTR1D 1983No 0.74 17 444 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.74 19 542 M. Rec5HTR1E P28566 HTR1E 2182 Yes 0.74 10 425 M. Rec 5HTR1F P30939 HTR1F 1805Yes 0.74 10 425 M. Rec 5HTR6 P50406 HTR6 3371 No 0.74 6 184 M. RecMBLP#1 Q9NR56 MBNL1 1293317 No 0.74 1 19 Unc MBLP#2 Q5VZF2 MBNL2 Yes0.74 1 19 Unc MBLP#3 Q9NUKO MBNL3 Yes 0.74 1 19 Unc Na-Dep P23975 SLC6A2222 Yes 0.64 18 194 Trans. noradrenaline Trans. Na-Dep P31645 SLC6A4 228No 0.64 35 262 Trans. serotonin Trans. Na-Dep Q01959 SLC6A3 238 No 0.6418 194 Trans. dopamine Trans. 002 D(2)DR P14416 DRD2 217 No 0.88 383 93M. Rec D(1A)DR P21728 DRD1 2056 No 0.88 33 20 M. Rec D(4)DR P21917 DRD4219 No 0.88 182 17 M. Rec D(1B)DR P21918 DRD5 1850 No 0.88 27 20 M. Rec5HTR1D P28221 HTR1D 1983 No 0.88 75 86 M. Rec 5HTR1B P28222 HTR1B 1898Yes 0.88 225 111 M. Rec 5HTR2A P28223 HTR2A 224 No 0.88 166 34 M. Rec5HTR2C P28335 HTR2C 225 No 0.88 111 23 M. Rec D(3)DR P35462 DRD3 234 No0.88 217 40 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.88 111 23 M. Rec 5HTR6P50406 HTR6 3371 No 0.88 33 52 M. Rec B2AR P07550 ADRB2 210 No 0.87 4397 M. Rec B1AR P08588 ADRB1 213 No 0.87 444 7 M. Rec B3AR P13945 ADRB3246 Yes 0.87 427 7 M. Rec A2aAR P08913 ADRA2A 1867 No 0.87 39 10 M. Rec003 D(2)DR P14416 DRD2 217 No 0.89 2724 112 M. Rec D(3)DR P35462 DRD3234 No 0.89 1579 46 M. Rec 5HTR1A P08908 HTR1A 214 No 0.87 1288 107 M.Rec 5HTR1B P28222 HTR1B 1898 Yes 0.87 1358 117 M. Rec D(1A)DR P21728DRD1 2056 No 0.87 252 20 M. Rec D(1B)DR P21918 DRD5 1850 No 0.87 181 20M. Rec 5HTR1D P28221 HTR1D 1983 No 0.86 549 86 M. Rec 5HTR1E P28566HTR1E 2182 No 0.86 442 72 M. Rec 5HTR1F P30939 HTR1F 1805 No 0.86 442 72M. Rec 5HTR6 P50406 HTR6 3371 No 0.85 484 54 M. Rec D(4)DR P21917 DRD4219 No 0.85 1030 17 M. Rec 5HTR2A P28223 HTR2A 224 No 0.85 1067 35 M.Rec 5HTR7 P34969 HTR7 3155 No 0.85 411 19 M. Rec 5HTR2C P28335 HTR2C 225No 0.85 636 24 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.85 636 24 M. Rec 0045HTR7 P34969 HTR7 3155 No 0.84 52 14 M. Rec 5HTR5A P47898 HTR5A 3426 No0.84 8 9 M. Rec 5HTR6 P50406 HTR6 3371 No 0.84 65 39 M. Rec D(2)DRP14416 DRD2 217 No 0.84 621 82 M. Rec D(1A)DR P21728 DRD1 2056 No 0.8448 19 M. Rec D(4)DR P21917 DRD4 219 No 0.84 311 16 M. Rec D(1B)DR P21918DRD5 1850 No 0.84 40 19 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.84 132 84M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.84 342 99 M. Rec 5HTR2A P28223HTR2A 224 No 0.84 285 32 M. Rec 5HTR2C P28335 HTR2C 225 No 0.84 217 21M. Rec D(3)DR P35462 DRD3 234 No 0.84 383 37 M. Rec 5HTR2B P41595 HTR2B1833 No 0.84 217 21 M. Rec 5HTR1A P08908 HTR1A 214 No 0.83 333 89 M. RecA2aAR P08913 ADRA2A 1867 No 0.81 75 9 M. Rec 005 D(2)DR P14416 DRD2 217No 0.77 1437 60 M. Rec D(4)DR P21917 DRD4 219 No 0.77 549 18 M. RecD(3)DR P35462 DRD3 234 No 0.77 850 37 M. Rec 5HTR1A P08908 HTR1A 214 No0.75 791 56 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.75 305 52 M. Rec 5HTR1BP28222 HTR1B 1898 No 0.75 847 61 M. Rec 5HTR2A P28223 HTR2A 224 No 0.75599 27 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.75 236 45 M. Rec 5HTR1FP30939 HTR1F 1805 No 0.75 236 45 M. Rec 5HTR7 P34969 HTR7 3155 No 0.75255 12 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.75 45 9 M. Rec 5HTR6 P50406HTR6 3371 No 0.75 417 87 M. Rec 5HTR2C P28335 HTR2C 225 No 0.75 368 15M. Rec 5HTR2B P41595 HTR2B 1833 No 0.75 368 15 M. Rec B2AR P07550 ADRB2210 No 0.73 19 7 M. Rec 006 5HT1IA P08908 HTR1A 214 No 0.88 338 102 M.Rec 5HTR1B P28222 HTR1B 1898 Yes 0.88 346 112 M. Rec 5HTR2A P28223 HTR2A224 No 0.86 299 33 M. Rec 5HTR2C P28335 HTR2C 225 No 0.86 230 22 M. Rec5HTR2B P41595 HTR2B 1833 No 0.86 230 22 M. Rec 5HTR6 P50406 HTR6 3371 No0.86 69 48 M. Rec D(2)DR P14416 DRD2 217 No 0.86 610 92 M. Rec D(1A)DRP21728 DRD1 2056 No 0.86 46 20 M. Rec D(4)DR P21917 DRD4 219 No 0.86 31517 M. Rec D(1B)DR P21918 DRD5 1850 No 0.86 40 20 M. Rec 5HTR1D P28221HTR1D 1983 No 0.86 131 85 M. Rec 5HTR7 P34969 HTR7 3155 No 0.86 56 16 M.Rec D(3)DR P35462 DRD3 234 No 0.86 377 38 M. Rec B2AR P07550 ADRB2 210No 0.85 536 7 M. Rec B1AR P08588 ADRB1 213 No 0.85 539 7 M. Rec 007D(2)DR P14416 DRD2 217 No 0.77 621 74 M. Rec D(1A)DR P21728 DRD1 2056 No0.77 50 18 M. Rec D(4)DR P21917 DRD4 219 Yes 0.77 334 15 M. Rec D(3)DRP35462 DRD3 234 No 0.77 400 36 M. Rec 5HTR6 P50406 HTR6 3371 No 0.75 6526 M. Rec 5HTR2A P28223 HTR2A 224 No 0.75 309 26 M. Rec D(1B)DR P21918DRD5 1850 No 0.74 44 18 M. Rec 5HTR2C P28335 HTR2C 225 No 0.74 237 15 M.Rec 5HTR2B P41595 HTR2B 1833 No 0.74 237 15 M. Rec AZaAR P08913 ADRA2A1867 No 0.72 84 8 M. Rec A2BAR P18089 ADRA2B 1942 No 0.72 84 8 M. RecA2CAR P18825 ADRA2C 1916 Yes 0.72 84 8 M. Rec MAPTau P10636 MAPT 1293224No 0.72 307 9 Unc HH1R P35367 HRH1 231 No 0.72 94 5 M. Rec 5HTR1D P28221HTR1D 1983 No 0.72 116 73 M. Rec 008 D(2)DR P14416 DRD2 217 No 0.79 53965 M. Rec 5HTR1A P08908 HTR1A 214 No 0.77 301 76 M. Rec 5HTR1B P28222HTR1B 1898 Yes 0.77 310 86 M. Rec D(4)DR P21917 DRD4 219 No 0.75 274 15M. Rec D(3)DR P35462 DRD3 234 No 0.75 324 36 M. Rec 5HTR2A P28223 HTR2A224 No 0.75 269 29 M. Rec 5HTR2C P28335 HTR2C 225 No 0.75 205 18 M. RecHH1R P35367 HRH1 231 No 0.75 99 5 M. Rec 5HTR2B P41595 HTR2B 1833 No0.75 205 18 M. Rec B2AR P07550 ADRB2 210 No 0.75 473 7 M. Rec B1ARP08588 ADRB1 213 No 0.75 475 7 M. Rec B3AR P13945 ADRB3 246 No 0.75 4557 M. Rec D(1A)DR P21728 DRD1 2056 No 0.75 38 18 M. Rec D(1B)DR P21918DRD5 1850 No 0.75 33 18 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.75 100 77M. Rec 009 5HTR2A P28223 HTR2A 224 No 0.83 773 28 M. Rec D(2)DR P14416DRD2 217 No 0.83 1942 74 M. Rec D(4)DR P21917 DRD4 219 No 0.83 721 18 M.Rec D(3)DR P35462 DRD3 234 No 0.83 1145 38 M. Rec 5HTR1A P08908 HTR1A214 No 0.8 1076 68 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.8 1130 76 M.Rec 5HTR1D P28221 HTR1D 1983 No 0.8 407 65 M. Rec 5HTR2C P28335 HTR2C225 No 0.8 478 16 M. Rec 5HTR1E P28566 HTR1IE 2182 No 0.8 335 54 M. Rec5HTR1F P30939 HTR1F 1805 No 0.8 335 54 M. Rec 5HTR7 P34969 HTR7 3155 No0.8 310 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.8 478 16 M. Rec 5HTR6P50406 HTR6 3371 No 0.8 568 69 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.8 5210 M. Rec D(1A)DR P21728 DRD1 2056 No 0.78 191 18 M. Rec 010 5HTR6P50406 HTR6 3371 No 0.82 383 55 M. Rec D(4)DR P21917 DRD4 219 No 0.82950 16 M. Rec D(2)DR P14416 DRD2 217 No 0.8 2423 73 M. Rec 5HTR1D P28221HTR1D 1983 No 0.8 487 74 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.8 1283 86M. Rec 5HTR2A P28223 HTR2A 224 No 0.8 959 32 M. Rec 5HTR7 P34969 HTR73155 No 0.8 465 14 M. Rec 5HTR1A P08908 HTR1A 214 No 0.8 1246 76 M. RecD(1A)DR P21728 DRD1 2056 No 0.8 189 19 M. Rec D(1B)DR P21918 DRD5 1850No 0.8 145 19 M. Rec 5HTR2C P28335 HTR2C 225 No 0.8 575 21 M. Rec D(3)DRP35462 DRD3 234 No 0.8 1516 37 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.8575 21 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.79 419 60 M. Rec 5HTR1FP30939 HTR1F 1805 Yes 0.79 419 60 M. Rec 011 5HTR1A P08908 HTR1A 214 No0.91 1137 78 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.91 1194 88 M. Rec5HTR6 P50406 HTR6 3371 No 0.9 361 44 M. Rec D(2)DR P14416 DRD2 217 No0.9 2285 86 M. Rec D(3)DR P35462 DRD3 234 No 0.9 1325 36 M. Rec D(4)DRP21917 DRD4 219 No 0.89 823 16 M. Rec 5HTR2A P28223 HTR2A 224 No 0.89803 30 M. Rec D(1A)DR P21728 DRD1 2056 No 0.89 239 19 M. Rec D(1B)DRP21918 DRD5 1850 No 0.89 181 19 M. Rec 5HTR2C P28335 HTR2C 225 Yes 0.88469 19 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.88 469 19 M. Rec A2aARP08913 ADRA2A 1867 No 0.88 54 9 M. Rec A2BAR P18089 ADRA2B 1942 Yes 0.8855 9 M. Rec A2CAR P18825 ADRA2C 1916 No 0.88 54 9 M. Rec CXCCRT3 P49682CXCR3 4441 No 0.86 90 63 M. Rec 012 5HTR6 P50406 HTR6 3371 No 0.84 48339 M. Rec 5HTR1A P08908 HTR1A 214 No 0.83 1292 68 M. Rec 5HTR1D P28221HTR1D 1983 No 0.83 522 69 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.83 133777 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.83 441 57 M. Rec 5HTR1F P30939HTR1F 1805 Yes 0.83 441 57 M. Rec 5HTR2A P28223 HTR2A 224 No 0.8 936 29M. Rec D(2)DR P14416 DRD2 217 No 0.78 2317 74 M. Rec D(4)DR P21917 DRD4219 No 0.78 909 15 M. Rec D(3)DR P35462 DRD3 234 No 0.78 1434 36 M. Rec5HTR2C P28335 HTR2C 225 No 0.78 563 18 M. Rec 5HTR7 P34969 HTR7 3155 No0.78 472 12 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.78 563 18 M. RecD(1A)DR P21728 DRD1 2056 No 0.78 173 18 M. Rec D(1B)DR P21918 DRD5 1850No 0.78 128 18 M. Rec 013 D(2)DR P14416 DRD2 217 No 0.9 430 95 M. RecD(1A)DR P21728 DRD1 2056 No 0.9 36 20 M. Rec D(4)DR P21917 DRD4 219 No0.9 235 17 M. Rec D(1B)DR P21918 DRD5 1850 No 0.9 32 20 M. Rec 5HTR1DP28221 HTR1D 1983 No 0.9 90 84 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.9274 111 M. Rec 5HTR2A P28223 HTR2A 224 No 0.9 207 33 M. Rec 5HTR2CP28335 HTR2C 225 No 0.9 150 22 M. Rec D(3)DR P35462 DRD3 234 No 0.9 26238 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.9 150 22 M. Rec 5HTR6 P50406HTR6 3371 No 0.9 46 57 M. Rec 5HTR7 P34969 HTR7 3155 No 0.89 29 16 M.Rec 5HTR1A P08908 HTR1A 214 No 0.88 267 101 M. Rec AZaAR P08913 ADRA2A1867 No 0.88 52 10 M. Rec A2BAR P18089 ADRA2B 1942 No 0.88 52 10 M. Rec014 5HTR1B P28222 HTR1B 1898 Yes 0.75 365 78 M. Rec D(2)DR P14416 DRD2217 No 0.74 631 57 M. Rec D(1A)DR P21728 DRD1 2056 No 0.74 53 18 M. RecD(4)DR P21917 DRD4 219 Yes 0.74 350 15 M. Rec D(3)DR P35462 DRD3 234 No0.74 413 33 M. Rec 5HTR2A P28223 HTR2A 224 No 0.74 333 25 M. Rec 5HTR2CP28335 HTR2C 225 No 0.74 259 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.74259 14 M. Rec 5HTR6 P50406 HTR6 3371 No 0.72 78 19 M. Rec 5HTR1D P28221HTR1D 1983 No 0.72 118 61 M. Rec 5HTR1A P08908 HTR1A 214 No 0.72 358 73M. Rec CP4502D6 P10635 CYP2D6 289 No 0.72 23 2 Enz CP4502J2 P51589CYP2J2 3491 No 0.72 23 2 Enz A2aAR P08913 ADRA2A 1867 No 0.72 91 8 M.Rec MAPTau P10636 MAPT 1293224 No 0.72 348 8 Unc 015 CP4502D6 P10635CYP2D6 289 No 0.78 22 2 Enz CP4502J2 P51589 CYP2J2 3491 No 0.78 22 2 EnzMAPTau P10636 MAPT 1293224 No 0.77 268 9 Unc D(4)DR P21917 DRD4 219 No0.77 311 15 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 314 25 M. Rec 5HTR2CP28335 HTR2C 225 No 0.77 249 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.77249 14 M. Rec MBLP#1 Q9NR56 MBNL1 1293317 No 0.75 227 3 Unc MBLP#2Q5VZF2 MBNL2 Yes 0.75 227 3 Unc MBLP#3 Q.9NUK0 MBNL3 Yes 0.75 227 3 Unc5HTR6 P50406 HTR6 3371 No 0.75 82 19 M. Rec D(2)DR P14416 DRD2 217 No0.73 564 57 M. Rec D(1A)DR P21728 DRD1 2056 No 0.73 49 18 M. Rec D(1B)DRP21918 DRD5 1850 Yes 0.73 42 18 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.73113 58 M. Rec 016 5HTR1A P08908 HTR1A 214 No 0.8 1056 43 M. Rec 5HTR1DP28221 HTR1D 1983 No 0.8 385 45 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.81103 50 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.8 314 36 M. Rec 5HTR1FP30939 HTR1F 1805 Yes 0.8 314 36 M. Rec D(2)DR P14416 DRD2 217 No 0.782111 59 M. Rec D(1A)DR P21728 DRD1 2056 Yes 0.78 129 18 M. Rec D(4)DRP21917 DRD4 219 No 0.78 718 15 M. Rec D(3)DR P35462 DRD3 234 No 0.781173 34 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 840 26 M. Rec 5HTR7P34969 HTR7 3155 No 0.75 367 10 M. Rec 5HTR2C P28335 HTR2C 225 No 0.71515 15 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.71 515 15 M. Rec 5HTR6P50406 HTR6 3371 No 0.71 287 35 M. Rec D(1B)DR P21918 DRD5 1850 No 0.6983 18 M. Rec 017 5HTR1A P08908 HTR1A 214 No 0.8 735 88 M. Rec 5HTR1BP28222 HTR1B 1898 Yes 0.8 781 98 M. Rec D(2)DR P14416 DRD2 217 No 0.771408 76 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 563 30 M. Rec 5HTR2CP28335 HTR2C 225 No 0.77 342 19 M. Rec D(3)DR P35462 DRD3 234 No 0.77752 37 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.77 342 19 M. Rec 5HTR6P50406 HTR6 3371 No 0.75 256 37 M. Rec MAPTau P10636 MAPT 1293224 No0.75 398 12 Unc D(4)DR P21917 DRD4 219 No 0.75 469 16 M. Rec 5HTR1DP28221 HTR1D 1983 No 0.75 263 84 M. Rec 5HTR7 P34969 HTR7 3155 No 0.75240 13 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.75 23 9 M. Rec 5HTR1E P28566HTR1E 2182 No 0.75 203 70 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.75 20370 M. Rec 018 5HTR2A P28223 HTR2A 224 Yes 0.94 384 39 M. Rec D(2)DRP14416 DRD2 217 No 0.94 823 160 M. Rec D(4)DR P21917 DRD4 219 No 0.94340 23 M. Rec D(3)DR P35462 DRD3 234 No 0.94 488 80 M. Rec D(1A)DRP21728 DRD1 2056 No 0.93 77 20 M. Rec D(1B)DR P21918 DRD5 1850 No 0.9360 20 M. Rec 5HTR2C P28335 HTR2C 225 No 0.92 208 26 M. Rec 5HTR7 P34969HTR7 3155 No 0.92 143 21 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.92 208 26M. Rec 5HTR1A P08908 HTR1A 214 No 0.92 420 161 M. Rec 5HTR1B P28222HTR1B 1898 Yes 0.92 442 169 M. Rec B2AR P07550 ADRB2 210 No 0.92 14 7 M.Rec B1AR P08588 ADRB1 213 No 0.92 14 7 M. Rec B3AR P13945 ADRB3 246 Yes0.92 14 7 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.92 179 127 M. Rec 0195HTR2A P28223 HTR2A 224 No 0.93 635 36 M. Rec D(2)DR P14416 DRD2 217 No0.92 1559 132 M. Rec 5HTR2C P28335 HTR2C 225 No 0.92 392 24 M. Rec 5HTR7P34969 HTR7 3155 No 0.92 228 19 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.92392 24 M. Rec B2AR P07550 ADRB2 210 No 0.91 18 7 M. Rec Bl AR P08588ADRB1 213 No 0.91 19 7 M. Rec 5HTR1A P08908 HTR1A 214 No 0.91 801 133 M.Rec B3AR P13945 ADRB3 246 Yes 0.91 18 7 M. Rec D(1A)DR P21728 DRD1 2056No 0.91 194 20 M. Rec D(4)DR P21917 DRD4 219 No 0.91 632 23 M. RecD(1B)DR P21918 DRD5 1850 No 0.91 160 20 M. Rec 5HTR1D P28221 HTR1D 1983No 0.91 315 101 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.91 841 141 M. RecHH1R P35367 HRH1 231 No 0.91 132 6 M. Rec

Synthetic Routes

Salt formation is undertaken thereafter in the above routes asnecessary, e.g. to give the benzoate, fumarate, citrate, acetate,succinate, halide, fluoride, chloride, bromide, iodide, oxalate, ortriflate salt. For example, the addition of hydrogen chloride wouldprovide the chloride salt and benzoic acid would give the benzoate salt.

In an embodiment, there is provided a method of synthesis of any of theherein described compounds. In an embodiment, there is provided a methodof synthesis of compound 001, 002, 003, 004, 005, 006, 007, 008, 009,010, 011, 012, 013, 014, 015, 016, 017, 018 or 019 as herein disclosed.

Further Characterisation of Compounds 018 and 019

cAMP

Compounds 018 (above, left) and 019 (above, right) were assayed using aserotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay, provided byMultispan. The reference used was 10 μM forskolin (a cAMP activator) tocalculate the percentage relative response, serotonin was used as thecontrol. The results can be seen in FIG. 1 . Compound 019 was activeagainst in all other receptor assays. The results indicate that compound019 stimulates the 5HT_(2a)R leading to downstream activation of cAMP,although the curve response seems atypical compared to the serotonincontrol.

IP₁

Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2creceptors) inositol phosphate 1(IP₁) assay, provided by Multispan. Thereference used was 1 μM serotonin to calculate the percentage relativeresponse. The results can be seen in FIG. 2 . Both compounds appear tosome activity against all three target receptors in this assay. This mayimply that the compounds do not activate any Gagni pathway.

Ca²⁺

Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2creceptors) calcium (Ca²⁺) assay, provided by Multispan. The referenceused was 10 μM serotonin to calculate the percentage relative responsein relative light units (RLU). The results can be seen in FIG. 3 . Bothcompounds have some activity against the 2a and 2c receptors.

B-Arrestin

Compounds 018 and 019 were assayed using a serotonin (1a, 1b, 2a and 2creceptors) B-arrestin assay, provided by DiscoverX. The reference usedwas 10 μM serotonin to calculate the percentage relative response. Theresults can be seen in FIG. 4 . In general, both compounds exhibitedsome activity in comparison to serotonin.

The compounds were also assayed in a serotonin 2b receptor B-arrestinassay, the results of which can be seen in FIG. 5 .

Reagent Information

B-Arrestin:

HTR1A PathHunter® eXpress HTR1A CHO-K1 β-Arrestin GPCR Assay93-0696E2CP0M

200 dp (2×96-well)

HTR1B PathHunter® eXpress HTR1B U2OS β-Arrestin GPCR Assay 93-0697E3CP6M

200 dp (2×96-well)

HTR2A PathHunter® eXpress HTR2A U2OS β-Arrestin GPCR Assay93-0401E3CP19M

200 dp (2×96-well)

HTR2C PathHunter® eXpress HTR2C U2OS β-Arrestin GPCR Assay 93-0289E3CP3M

200 dp (2×96-well)

Multispan β-arrestin assay with CHO-K1-5HT_(2b)R cells—Catalog C1350-1a

Homogeneous Time Resolved Fluorescence (HTRF) and Calcium:

IP-One Gq kit—cisbio—cat. No. 62IPAPEB

cAMP Gs dynamic kit—cisbio—cat. No. 62AM4PEC

FLIPR calcium 6 assay explorer kit—VWR—cat. No. MLDVR8190

Cells Used in HTRF and Calcium Assays:

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor,Catalog DC1319a

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor,Catalog DC1320a

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5HT1B Receptor,Catalog DC1320a

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor,Catalog DC1324-1

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor,Catalog DC1325-1

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor,Catalog DC1326-1

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor,Catalog DC1334

For the B-arrestin assays the cells came with the kits apart from the 2breceptor assay (Valiscreen serotonin 5HT-2B (human) cell line—ES-314-C,Perkin Elmer).

The invention claimed is:
 1. A method of treatment of a subject,comprising administering a compound or pharmaceutically acceptable saltthereof to the subject, wherein the subject has depression, anxiety, ora pain condition, and wherein the compound is selected from:


2. The method according to claim 1, wherein the subject is a human. 3.The method according to claim 1, wherein the subject has depression. 4.The method according to claim 3, wherein the subject hastreatment-resistant depression.
 5. The method according to claim 3,wherein the compound or pharmaceutically acceptable salt thereof isadministered together with a complementary treatment, and thecomplementary treatment is psychotherapy.
 6. The method according toclaim 1, wherein the subject has anxiety.
 7. The method according toclaim 1, wherein the subject has a pain condition.
 8. The methodaccording to claim 7, wherein the subject has a chronic pain condition.9. The method according to claim 1, wherein the compound orpharmaceutically acceptable salt thereof is administered one or moretimes a month.
 10. The method according to claim 1, wherein the compoundor pharmaceutically acceptable salt thereof is administered orally,buccally, sublingually, transdermally, sublabially, by inhalation,intravenously, or rectally.
 11. The method according to claim 1, whereinthe compound or pharmaceutically acceptable salt thereof is administeredas a composition in a dosage form selected from a tablet, a capsule,granules, powder, an aerosol, an injectable liquid, or a suppository.12. The method according to claim 1, wherein the compound orpharmaceutically acceptable salt thereof is administered together with acomplementary treatment, a further active agent, or both a complementarytreatment and a further active agent.
 13. A method of treatment of asubject, comprising administering to the subject a compositioncomprising a pharmaceutically effective amount of a compound orpharmaceutically acceptable salt thereof, wherein the subject hasdepression, wherein the composition is formulated in a dosage formselected from a tablet, a capsule, granules, powder, an aerosol, andinjectable liquid, or a suppository, and wherein the compound isselected from:


14. The method according to claim 13, wherein the subject hastreatment-resistant depression.
 15. The method according to claim 13,wherein the composition is administered by inhalation.
 16. The methodaccording to claim 13, wherein the composition comprises a dosage amountof the compound or pharmaceutically acceptable salt thereof in the rangeof 0.05 mg to 100 mg.
 17. The method according to claim 13, wherein thecomposition comprises a dosage amount of the compound orpharmaceutically acceptable salt thereof in the range of 0.1 mg to 50mg.
 18. The method according to claim 13, wherein the composition isadministered with a complementary treatment, and the complementarytreatment is psychotherapy.